Total synthesis of (-)-ophiodilactone A and (-)-ophiodilactone B

Article abstract of DOI:10.1002/anie.201307835

The first asymmetric total synthesis of (-)-ophiodilactone A and (-)-ophiodilactone B, isolated from the ophiuroid (Ophiocoma scolopendrina), is reported. The key features of the synthesis include the highly stereocontrolled construction of the structurally congested γ-lactone/δ-lactone skeleton through an asymmetric epoxidation, diastereoselective iodolactonization, and intramolecular epoxide-opening with a carboxylic acid, and biomimetic radical cyclization of ophiodilactone A to ophiodilactone B. Bioinspired synthesis: The first total synthesis of the title compounds has been accomplished in a highly stereocontrolled manner. Key features of the synthesis include an asymmetric epoxidation, a diastereoselective iodolactonization, an intramolecular epoxide opening with a carboxylic acid, and a biomimetic radical cyclization of ophiodilactone A to ophiodilactone B. Copyright

Full text of DOI:10.1002/anie.201307835

Angewandte
Chemie
DOI: 10.1002/anie.201307835
Natural Product Synthesis
Total Synthesis of (À)-Ophiodilactone A and (À)-Ophiodilactone B**
Takaaki Matsubara, Keisuke Takahashi, Jun Ishihara, and Susumi Hatakeyama*
Abstract: The first asymmetric total synthesis of (À)-ophiodi-
lactone A and (À)-ophiodilactone B, isolated from the ophiu-
roid (Ophiocoma scolopendrina), is reported. The key features
of the synthesis include the highly stereocontrolled construc-
tion of the structurally congested g-lactone/d-lactone skeleton
through an asymmetric epoxidation, diastereoselective iodo-
lactonization, and intramolecular epoxide-opening with a car-
boxylic acid, and biomimetic radical cyclization of ophiodi-
lactone A to ophiodilactone B.
Matsunaga and co-workers proposed that ophiodilac-
tone B (2) would be directly biosynthesized from ophiodilac-
tone A (1) through a radical cyclization.[1] Inspired by this
hypothesis, we envisioned 1 as a precursor of 2 (Scheme 1).
Since, to our knowledge, such an intramolecular radical
I
n 2009, Matsunaga and co-workers reported the isolation of
ophiodilactones A (1) and B (2) from Ophiocoma scolopen-
drina, a tropical and subtropical ophiuroid widely distributed
in the Indo-Pacific. These compounds exhibit moderate
cytotoxic activity against P388 murine leukemia cells with
IC50 values of 5.0 and 2.2 mgmLÀ1, respectively.[1] Intensive
NMR studies led to the determination of their characteristic
compact structures consisting of a fused g-lactone/d-lactone
skeleton with four phenyl groups and four or five contiguous
stereogenic centers containing three quaternary centers. The
absolute structures of 1 and 2 were tentatively determined
based on the analysis of the CD-spectroscopic data of 1.[1]
Scheme 1. Retrosynthetic analysis.
coupling between a benzene ring and a d-lactone with site
selectivity is unprecedented,[3,4] it would be a very challenging
goal to accomplish this radical process. From a retrosynthetic
perspective, we assumed that ophiodilactone A (1) would be
accessible from 3 by intramolecular epoxide opening with
a carboxylic acid group with inversion of stereochemistry. To
access 3 we envisioned hydrogenation of 4, which was
expected to preferentially proceed with desired diastereose-
lectivity as depicted in 4’.[5] We reasoned that compound 4
could be accessed from 6 via 5 by an approach involving
diastereoselective iodolactonization and addition of phenyl
and acetic acid units.
Their unique highly substituted dilactone structures and
biological activities prompted us to investigate the synthesis
of ophiodilactones.[2] Herein we describe the first total
synthesis of (À)-ophiodilactone A (1) and (À)-ophiodilac-
tone B (2), thereby unambiguously determining their abso-
lute structures.
[*] T. Matsubara, Dr. K. Takahashi, Dr. J. Ishihara,
Prof. Dr. S. Hatakeyama
In our preliminary study,[2] we have developed an eight-
step synthesis of 6 from Meldrumꢀs acid through Stille
coupling[6] of 7 with 8[7] and Katsuki–Sharpless asymmetric
epoxidation[8] of 10 (Scheme 2). Although the diastereoselec-
tivity and overall yield of this synthesis were satisfying, its
enantioselectivity was disappointingly low (35% ee). There-
fore, we first devoted our efforts to improving the asymmetric
epoxidation step. After considerable experimentation,[9] we
eventually found that the method developed by Yamamoto
and co-workers[10] afforded epoxy alcohol 11 in acceptable
enantioselectivity and yield although it proceeded very
Graduate School of Biomedical Sciences, Nagasaki University
1-14 Bunkyo-machi, Nagasaki 852-8521 (Japan)
E-mail: susumi@nagsaki-u.ac.jp
[**] We thank Prof. Shigeki Matsunaga (The University of Tokyo) for
providing us copies of CD spectra of ophiodilactones A and B. This
work was supported by the Grant-in-Aid (25253002 and 24659009)
from JSPS and the Grant-in-Aid for Scientific Research on Innovative
Areas “Advanced Molecular Transformations by Organocatalysis”
(No. 2304) (24105526) and “Organic Synthesis based on Reaction
Integration” (No. 2105) (24106736) from MEXT.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307835.
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Scheme 2. Reagents and conditions: a) PhCH2COCl, pyridine, CH2Cl2,
then MeOH, reflux, 99%; b) PhCH2Br, NaH, benzene/DMF, 858C,
82%; c) Tf2O, 5m LiOH, hexane, 08C, 93%; d) 8, [Pd(PPh3)4]
(0.1 equiv), CuCl, LiCl, DMSO, 808C, 94%; e) DIBAL-H, CH2Cl2,
À788C, 97%; f) tBuOOH, 13 (0.1 equiv), VO(OiPr)3 (0.05 equiv),
toluene, 08C, 89%; g) Dess–Martin periodinane, NaHCO3, CH2Cl2;
h) NaClO2, NaH2PO4, 2-methyl-2-butene, tBuOH/H2O, 08C; i) I2, aq
NaHCO3, CH2Cl2, 08C; j) 20m NaOH, THF, 508C, then H2SO4, 08C,
94% (15:1 mixture), 65% (enantiomerically pure 5 after recrystalliza-
tion) from 11 (4 steps).
Scheme 3. Reagents and conditions: a) (COCl)2, DMSO, CH2Cl2,
À788C, then Et3N; b) PhMgCl, THF, À408C, 81% (2 steps); c) Dess–
Martin periodinane, NaHCO3, CH2Cl2, 92%; d) Me3SiCH2CO2tBu,
LHMDS, HMPA, À788C, 94%; e) TFA/CH2Cl2 (1:10), 608C; f) H2,
20% Pd(OH)2/C, AcOEt, 08C; g) HOCH2CH2OH, 1508C, 55% from 17
(3 steps); h) H2O, 1508C, sealed tube, 40%.
sluggishly. Thus, when compound 10 was reacted with tert-
butyl hydroperoxide using 13 (0.1 equiv) and VO(OiPr)3
(0.05 equiv) in toluene at 08C for 6 days, 11 was obtained in
79% ee[11] and 89% yield. The use of 14 in place of 13 resulted
in comparable enantioselectivity (78% ee) albeit the yield
became lower (60%). Compound 11 was then subjected to
Dess–Martin oxidation followed by Pinnick–Kraus oxidation
to provide carboxylic acid 6 cleanly. Upon successive iodo-
lactonization, alkaline hydrolysis, and acidic lactonization, 6
afforded g-lactones 5 and 12 in a ratio of 15:1 in 94% yield
from 11. Interestingly, the ratio turned out to be sensitive to
the final acidic lactonization conditions. When this process
was carried out at 808C rather than 08C, the ratio diminished
to 6:1,[2] implying the partial intervention of the C4 tertiary
carbocation during lactonization of the corresponding dihy-
droxy carboxylic acid. At this stage enantiomerically pure 5
was obtained after recrystallization from benzene (65% from
11). An X-ray structure[12] of the mesylate derived from 5
allowed us to unambiguously determine the absolute config-
uration of 5 as depicted.
With the desired g-lactone 5 in hand, we next investigated
the synthesis of ophiodilactone A (1; Scheme 3). Compound 5
was subjected to Swern oxidation followed by Grignard
reaction using phenylmagnesium chloride to give alcohol 15,
which was then oxidized to 16. Peterson olefination[13] of 16
proceeded smoothly to afford unsaturated ester 17 in 94%
yield with excellent E selectivity, whereas either Horner–
Wadsworth–Emmons or Wittig olefination did not produce 17
at all. As expected from the conformational analysis by
molecular mechanics calculations, 17 did not undergo hydro-
genation because of the steric bulkiness of the tert-butyl ester
group. In fact, we successfully obtained the hydrogenated
compound 3 from sterically less hindered carboxylic acid 4.
Notably, this hydrogenation took place with excellent diaste-
reoselectivity at 08C and the corresponding C5-epimer 18 was
1
not observed in the H NMR, whereas the reaction at room
temperature afforded a 7:1 mixture of 3 and 18. To complete
the total synthesis of ophiodilactone A (1), we explored the
crucial intramolecular epoxide-opening reaction of 3 under
various conditions (Table 1). Even acid-catalyzed conditions
required higher temperatures, which caused the partial
decomposition of 3 or 1 leading to the lower yield of
Table 1: Synthesis of ophiodilactone A from 3.
Entry Conditions
Yield [%][a]
0[c]
1[b]
CSA (1 equiv), TFA (5equiv), CH2Cl2, 1608C, 4 h,
sealed tube
2
3
4
5
TFA, 1008C, 3 days, sealed tube
TFA, 1508C, 4 h, sealed tube
H2O, 1508C, 12 h, sealed tube
HOCH2CH2OH, 1508C, 5 h
15
38
50
55
[a] Overall yield from 17 (3 steps). [b] Conditions reported by Trost and
Krische for the similar cyclization.[17] [c] Compound 3 was recovered in
50% yield. CSA=camphorsulfonic acid.
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1 (Table 1, entries 1–3). However, we gratifyingly found that
the epoxide-opening reaction proceeded under neutral con-
ditions when 3 was simply heated at 1508C in a protic solvent
such as water and ethylene glycol (Table 1, entries 4,5).[14,15]
The best result was obtained under the conditions listed in
entry 5, which produced (À)-ophiodilactone A (1) in 55%
yield from 17. The spectral data of the synthetic ophiodilac-
tone A were identical to those of the natural specimen[1] in all
respects. It is important to add that upon exposure of 18[16] to
the conditions listed in entry 4, the cyclization took place
sluggishly to produce 5-epi-ophiodilactone (19). The compar-
ison of the spectral data of 1 and 19 allowed us to further
confirm that hydrogenation of 4 occurred with desired
diastereofacial selectivity.
Keywords: asymmetric synthesis · bioinspired synthesis ·
radical coupling · total synthesis
.
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À
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To achieve biomimetic transformation of ophiodilac-
tone A (1) to ophiodilactone B (2), we focused on direct
À
oxidative coupling reactions of C H and Ar–H bonds.
Although such reactions have been widely investigated, they
were mostly executed under basic conditions.[4] However,
owing to the extreme instability of 1 under basic conditions,
we had to intensively seek appropriate neutral or weekly
acidic conditions for our endgame. As a result, we found that
when
a solution of 1 in toluene was heated with
ˇ
Moody, V. Franckevicius, P. Drouhin, J. E. M. N. Klein, R. J. K.
Cu(OAc)2·H2O (0.1 equiv) at 2008C under oxygen by mod-
ifying the procedure reported by Taylor and co-workers,[4g,18]
the radical cyclization cleanly took place to furnish (À)-
ophiodilactone B (2) in 75% yield (Scheme 4). The reaction
Taylor, Tetrahedron Lett. 2012, 53, 1897.
[5] Conformer 4’ was suggested to be the energetically most stable
by molecular mechanical calculations (MMFF, Macro Model
8.6). Other optimum thirteen conformers within 3.0 kcalmolÀ1
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olefinic double bond.
[6] X. Han, B. M. Stoltz, E. J. Corey, J. Am. Chem. Soc. 1999, 121,
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[7] Prepared from styrene: 1) CHBr3, 50% NaOH; 2) EtMgBr,
THF; 3) nBu3SnH, B(C6F5)3, toluene. See the Supporting
Information.
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[11] Determined by HPLC analysis of 5 on a chiral stationary phase.
[12] CCDC 950641 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
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Scheme 4. Synthesis of ophiodilactone B.
proceeded with excellent site selectivity and no other cyclized
products were observed. Note that when the reaction was
conducted at 1708C, the yield was dramatically diminished to
6% and the unreacted 1 was recovered in 91% yield. The
synthetic ophiodilactone B exhibited spectral properties
identical in all respects to those reported for the natural
product.[1]
In conclusion, we have accomplished the first total
synthesis of (À)-ophiodilactone A (1) and (À)-ophiodilac-
tone B (2) in enantiomerically pure forms in 14% (17 steps)
and 10% (18 steps) overall yields from Meldrumꢀs acid,
respectively. The present work illustrates the prowess of the
copper-catalyzed radical cyclization to enable biomimetic
transformation of 1 to 2.
Received: September 6, 2013
Revised: October 16, 2013
Published online: December 11, 2013
[14] In light of the model reported by Jamison and Vilotijevic of
epoxide-opening reactions promoted by water or ethylene
glycol, we assumed that the reaction of 3 to 1 would be
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accelerated by hydrogen-bond activation. I. Vilotijevic, T. F.
Jamison, Science 2007, 317, 1189.
[16] Compound 18 was partly obtained in pure form from a 7:1
mixture of 3 and 18 by preparative TLC (SiO2, AcOEt) albeit
poor separation was achieved.
[17] B. M. Trost, M. J. Krische, J. Am. Chem. Soc. 1999, 121, 6131.
[18] When the reaction was conducted using Cu(OAc)2·H2O
(0.1 equiv) in mesitylene at 1658C for 5 h under O2 according
to the method reported by Taylor and co-workers,[4g] ophiodi-
lactone B was not produced but appreciable decomposition of
1 was observed.
[15] For related epoxide-opening reactions, see: a) Z. Wang, Y.-T.
Cui, Z.-B. Xu, J. Qu, J. Org. Chem. 2008, 73, 2270; b) J. M. Wurst,
G. Liu, D. S. Tan, J. Am. Chem. Soc. 2011, 133, 7916; c) J. J.
Mousseau, C. J. Morten, T. F. Jamison, Chem. Eur. J. 2013, 19,
10004.
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